US3551413A - Benzo-lactams - Google Patents

Benzo-lactams Download PDF

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Publication number
US3551413A
US3551413A US806697A US3551413DA US3551413A US 3551413 A US3551413 A US 3551413A US 806697 A US806697 A US 806697A US 3551413D A US3551413D A US 3551413DA US 3551413 A US3551413 A US 3551413A
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Prior art keywords
methyl
lower alkyl
tetrahydro
formula
hydrochloride
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Expired - Lifetime
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US806697A
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English (en)
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John Krapcho
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • New compounds having the general formula wherein X and X are the same or different and can be hydrogen, lower alkyl, lower alkoxy and halogen; R can be lower alkyl, lower alkenyl, aryl loweralkyl, and aryl loweralkenyl; A is lower alkylene; and
  • n is 0 or 1.
  • These compounds are useful as central nervous system stimulants.
  • This invention relates to new compounds of the formula:
  • X and X are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, and lower alkoxy;
  • R is selected from the group consisting of lower alkyl, lower alkenyl, aralkyl, and aralkenyl;
  • R and R are hydrogen and together 1s 0x0 (0:);
  • A is alkylene;
  • B is a basic nitrogen containing radical of less than fourteen carbons;
  • p is l, 2 tor 3; mislor2;andnis0or1.
  • B is further defined as a nitrogen contaimng radical having the formula wherein R and R are the same or different and are selected from the group consisting of hydrogen, lower alkyl, cyclopropylmethyl, alkene (e.g., allyl, 3,3-dimethylallyl); alkyne (e.g., propargyl), X-substituted phenyl;
  • R and R are saturated heterocychcs having ice five to seven atoms in the ring.
  • Heterocyclics represented by R and R are those having the formula in which X represents NR CHR O or S, t represents 1, 2 or 3 and R and R represent hydrogen, lower alkyl, hydroxy-lower alkyl, alkanoyloxy-lower alkyl,
  • alkanoyloxy-lower alkoxy lower alkyl hydroxy-lower alkoxy-lower alkyl, di(lower alkyl)-amino-lower alkyl,
  • homopiperadino and homopiperazino and substituted homopiperazino e.g., N ethylhomopiperazino, N benzylhomopiperazino, and N -(hydroxyethyl)homopiperazino
  • the preferred compounds are those compounds wherein m is 1, n is 0, R and R together is oxo; R is lower alkyl; A is a two-carbon alkylene; and B is diethylamino or morpholino.
  • lower alkyl, lower alkoxy, and lower alkylene as employed herein include both straight and branched chain radicals of from one to eight carbon atoms and halogen is preferably chloro or brorno.
  • alkanoyloxy includes radicals of up to fourteen carbon atoms.
  • the new bases of Formula I form acid-addition salts by reaction with the common inorganic and organic acids.
  • inorganic salts as the hydrohalides, e.g., hydrobromide, hydrochloride, hydroiodide, sulfates, nitrates, phosphates, and so forth, and organic salts as acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate, salicylate, theophyllinate, camphorsulfonate, alkanesulfonate e .g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, toluenesulfonate, and the like, are also 'within the scope of the invention. It is frequently convenient to effect the purification of the product by forming the acid salt.
  • the base may be obtained therefrom by neutralization with an alkali hydroxide such as sodium
  • the bases of Formula I also form quaternary ammonium salts, e.g., lower alkyl halides such as methyl chloride, methyl bromide, ethyl chloride, and so forth, lower alkyl sulfates such as methyl sulfate, ethyl sulfate, and so forth, monocyclic aryl(lower alkyl)halides and sulfates such as benzyl bromide, benzyl sulfate, and so forth. This is accomplished by reacting the base with the alkyl halide, sulfate, or the like.
  • lower alkyl halides such as methyl chloride, methyl bromide, ethyl chloride, and so forth
  • lower alkyl sulfates such as methyl sulfate, ethyl sulfate, and so forth
  • monocyclic aryl(lower alkyl)halides and sulfates such as
  • the compounds of this invention are therapeutically active compounds which possess central nervous system stimulant activity and hence are utilizable in the treatment of depression and also have control of obesity.
  • the compounds of this invention can be administered peroxally, the dosage for such treatment being adjusted for the activity of the particular compound employed. It is understood that the dosage may be administered from 0.01 to 100 mgs. per kg. of the mallian host being treated.
  • the compounds of this invention, wherein R and R are hydrogen also possess central nervous system modification activity.
  • the new compounds of Formula I are produced by converting a cyclic ketone of Formula II to compounds of Formula III by treatment with sodium azide in a medium such as acetic acid followed by concentrated sulfuric acid or by conversion of II to an oxime and then rearranging the oxime to the desired compound of Formula III by a Beckmann rearrangement, e.g., by treatment with an arylsulfonyl halide such as benzenesulfonyl chloride in a hydrogen halide acceptor such as pyridine (CII2)n 91:0
  • amido end product may be reduced as by reacting it with lithium aluminum hydride to form the end product wherein R and R are hydrogen.
  • EXAMPLE 1 3-(2-diethylaminoethyl)-3,4-dihydro-1-methyl-3- phenylcarbostyril, hydrochloride
  • A Preparation of 3,4 dihydro -1-methyl-3-phenylcarbostyril.--A suspension of 22.0 g. of 3-phenylhydrocarbostyril in 200 ml. of toluene is added to a suspension of 3.9 g. of sodamide in 250 m1. of toluene. The mixture is refluxed for thirty minutes, cooled to room temperature and treated with 25.0 g. of dimethylsulfate. The mixture is refluxed for 2.5 hours, cooled and treated with 200 ml. of water.
  • the aqueous phase is discarded and the organic phase extracted with a cold solution of 5 ml. of concentrated hydrochloric acid in 100 ml. of water.
  • the aqueous layer is separated, treated with a solution of 4 g. of sodium hydroxide in 20 ml. of water and the free base extracted with ether.
  • the ethereal solution is dried over magnesium sulfate, filtered and the solvent evaporated to give 3.2 g. of base.
  • the latter is dissolved in 15 ml. of absolute alcohol, treated with 1.5 ml. of 7.7 N alcoholic hydrogen chloride and the solution diluted to 100 ml. of ether to give 2.0 g. of product, M.P. 198.
  • the colorless material weighs 1.5 g., M.P. 198- 200.
  • EXAMPLE 2 4- (2-diethylaminoethyl) -3,4,5,6-tetrahydro-l-methyl- 4-phenyl-1-benzazocin-2( 1H) -one, hydrochloride Following the procedure of Example 1 but utilizing an equivalent amount of 3,4,5,6-tetrahydro-4-pheny1-1- benzazocin-2(H)-one (prepared in accordance with the procedures set forth in copending application, Ser. No. 418,910, filed Dec. 16, 1964, and now U.S. Pat. No.
  • EXAMPLE 3 4-( 3-piperidinopropyl) -3,4,5 ,6-tetrahydro-1-methyl-4- phenyl-1-benzazocine-2( 1H) -one, hydrochloride Following the procedure of Example 1 but utilizing equivalent amounts of 3,4,5,6-tetrahydro-4-phenyl-1- benzaZocin-2-(1H)-one in lieu of S-phenylcarbostyril in part A and 3-piperidinopropyl in lieu of 2-diethylaminoethyl chloride in part B, the desired product is recovered.
  • EMMPLE 7 4 (3 piperidinopropyl) 3,4,5,6 tetrahydro 4 (ochlorophenyl) 1 propyl 1-benzazocin-2(1H)-one, hydrochloride (A) 3,4,5,6 tetrahydro-4-(o-chlorephenyl)-1-propyl- 1-benzazocin-2(H)-one.--Following the procedure of Example 1 (A) but utilizing 3,4,5,6-tetrahydro-4-(o-chlorophenyl)-1-benzazocin-2(1H)-one in lieu of 3-phenylcarbostyril and propyl iodide instead of dimethylsulfate, a crystalline material is recovered.
  • EXAMPLE 8 4-[2-(1-hexamethy1enimino)ethyl]-3,4,5,6 --tetrahydro 1 benzyl 4 o tolyl 1 benzazocin 2(1H) one, hydrochloride 6
  • EXAMPLE 9 3-[3- (4-methylpiperazino) propyl] -4,5-dihydro-1-methyl- 3-o-methoxyphenyl-1H-l-benZazepin-2-(3H) -one, hydrochloride (A) 4,5-dihydro-l-methyl 3 o methoxyphenyl-lH- l-benzazepin-2(3H)-one.-Following the procedure of Example 1(A) but substituting 4,5-dihydro-3-o-methoxy phenyl-lH-1-benzazepin-2(3H)-one, there is a crystalline product.
  • EXAMPLE 12 3- (Z-diethylaminoethyl) -4,5-dihydro-1-methyl-3- (pmethoxyphenyl) 1 S-methyllH- lbenzazepin- 2 (3H) -one, hydrochloride
  • 3-phenylhydrocarbostyril By replacing the 3-phenylhydrocarbostyril with 4,5-dihydro-3-(p-methoxyphenyl) 8 methyl-lH-l-benzazepin-2(3H)-one in Example 1, there is obtained 3(2-dimethylaminoethyl) 4,5 dihydro 1 methyl-S-(p-methoxyphenyl) 8 methyl-1H-1-benzazepin-2(3H)-one. hydrochloride.
  • EXAMPLE 13 4-(2-diethylaminoethyl)-1,3,4,5-tetrahydro-1-methyl-4- phenyl-l-benzazocin-Z 1H)-one, methiodide
  • the reaction mixture is allowed to stand at room temperature and the solvent is removed under reduced pressure.
  • the residue is triturated with anhydrous ether and crystallized from a mixture of ethanol and ether.
  • EXAMPLE 14 3-[2- (diethylamino) ethyl] -l ,2,3 ,4-tetrahydrol -methyl-3- phenylquinoline, hydrochloride Treating 5.0 grams of the product of Example 1(B) with lithium aluminum hydride yields 3-[2-(diethylamino)ethyl] 1,2,3,4 tetrahydro 1 methyl-3-phenylquinoline, hydrochloride.
  • EXAMPLE 15 4-(2-diethylaminoethyl) -1,3,4,5-tetrahydro-1-rnethyl-4- phenyl-ZH-l-benzazepin-2-one (A) 1,3,4,5-tetrahydro l methyl-4-phenyl-2H-l-benzazepin-Z-one.Substituting l,3,4,5-tetrahydro-l-methyl- 7 4-phenyl-2H-l-benzazepin-Z-one in the procedure of Example 1(A), the product is recovered.
  • R and R are selected from the group consisting of hydrogen, lower alkyl, cyclopropylrnethyl,
  • a compound having a formula in accordance with claim 2 having the name 4-(2-diethylaminoethyl)-3,4,5,6- tetrahydro-l-methyl-4-phenyl- 1-benzaz0cin-2( 1H) -one.
  • a compound having a formula in accordance with claim 1 having the name 4-(3-piperidinopropyl)-3,4,5,6- tetrahydro-1-rnethyl-4-phenyl-1-benzazocin-2-(1H)-one.
  • a compound having a formula in accordance with claim 5 having the name 3-(2-diethylaminoethyl)-4,5-dihydro-1-methyl-3-phenyl-1H-1-benZazepin-2(3H)-one.
  • a compound having a formula in accordance with claim 7 having the name 4-(2-diethylaminoethyl)-l,3,4,5- tetrahydro-l-methyl-4-pheny1-2H-l-benzazepin-Z-one.
  • a compound in accordance with claim 1 having the name 3-[2-(diethylamino)ethyl]-l,2,3,4-tetrahydro-1- methyl-3-phenylquinoline, hydrochloride.
  • a compound in accordance with claim 1 having the name 3-(2-diethylaminoethyl)-3,4-dihydro-1-methyl-3- phenylcarbostyril, hydrochloride.
  • alkyryl should read-alkynyl-.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US806697A 1969-03-12 1969-03-12 Benzo-lactams Expired - Lifetime US3551413A (en)

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US80669769A 1969-03-12 1969-03-12

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US (1) US3551413A (fr)
CA (1) CA924718A (fr)
CH (1) CH522648A (fr)
DE (1) DE2007468A1 (fr)
FR (1) FR2034846B1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4778793A (en) * 1985-07-20 1988-10-18 Hoechst Aktiengesellschaft Dihydroquinolinone derivatives, processes for their preparation, medicaments containing them and their use, and intermediate products for their preparation
US6855726B1 (en) 1998-03-31 2005-02-15 Warner-Lambert Company Llc Quinolones as serine protease inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4801593A (en) * 1979-09-13 1989-01-31 Burroughs Wellcome Co. Chemotherapeutic agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4778793A (en) * 1985-07-20 1988-10-18 Hoechst Aktiengesellschaft Dihydroquinolinone derivatives, processes for their preparation, medicaments containing them and their use, and intermediate products for their preparation
US6855726B1 (en) 1998-03-31 2005-02-15 Warner-Lambert Company Llc Quinolones as serine protease inhibitors

Also Published As

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DE2007468A1 (de) 1970-09-24
FR2034846A1 (fr) 1970-12-18
CH522648A (fr) 1972-06-30
FR2034846B1 (fr) 1974-02-01
CA924718A (en) 1973-04-17

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